The nuclear envelope: emerging roles in development and disease

The chromosomes of eukaryotic cells are separated from the cytoplasm by the nuclear envelope. The nuclear envelope includes two riveted membranes, plus embedded pore complexes that mediate nuclear import and export. In this sense, the nuclear envelope is truly a border zone. However, the envelope also links directly to chromosomes, and anchors two major infrastructures--the nuclear lamina and Tpr filaments--to the nuclear perimeter. Proteins of the nuclear envelope mediate a variety of fundamental activities, including DNA replication, gene expression and silencing, chromatin organization, cell division, apoptosis, sperm nuclear remodeling, the behavior of pronuclei, cell fate determination, nuclear migration and cell polarity. Furthermore, mutations in nuclear lamins and lamin-binding proteins cause tissue-specific inherited diseases. This special issue of Cell and Molecular Life Sciences is devoted to recent major advances in the characterization of nuclear envelope proteins and their roles. We offer here an overview of the topics covered in this issue of CMLS, and also discuss the emerging recognition that the nuclear envelope is an organelle critical for a wide range of genetic and developmental activity in multicellular organisms.     

Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.     

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.     

Differences in cerebral morphology in 2 stocks of mutant mice heterozygous for the loop-tail (Lp)-gene

Summary Adult loop-tail heterozygotes (Lp/+) from a stock ofLp-mice which consistently fail to show head wobbling exhibit normal brain morphology with respect to size and shape of lateral ventricles and nearby nuclei. Loop-tail heterozygotes from a head wobbling stock ofLp-mice show enlargement and deformity of the lateral ventricles.Supported by research grant HD09562 from the National Institutes of Health.     

Chronic mercury vapor poisoning of aphids

Summary Exposure of green peach aphids,Myzus persicae (Sulz.), to an atmosphere containing mercury vapor resulted in a curtailment ofembryogenesis and larviposition by adults, and in the development by larvae and adults of a cuticular darkening of their legs, head capsule, antennae, cornicles and cauda. Mortality of affected larvae resulted from molting difficulties, particularly by last-instar alatiform female and male larvae. Greenbugs,Schizaphis graminum (Rond.), and pea aphids,Acyrthosiphon pisum (Harr.), responded to mercury vapor exposure in similar ways.     

Synaptic vesicle depletion and glutamate uptake in a nerve-muscle preparation of the locust,Locusta migratoria L

Summary Excitatory terminals, depleted of their synaptic vesicles by stimulation at high frequency, were incubated in the radiolabelled putative neurotransmitter, L-glutamate. Quantitative electron microscope autoradiography revealed that the axoplasm of these recovering terminals had accumulated the³H L-glutamate.Acknowledgment. The authors wish to thank Dr N. M. Blackett for running the computer analyses of the autoradiographical results. R. P. Botham gratefully acknowledges the SRC for financial assistance.     

Familial association in serum IgE levels.

The serum IgE levels measured by RIST correlated closely with those obtained by the single radioimmunodiffusion method. Values for husband and wife were closely related as were those between father and daughter but in contrast to previous observations no significant relationship existed between IgE levels for mother and son.     

Stimulation induced depletion of the synaptic vesicles in excitatory motor nerve terminals of the locust,Locusta migratoria L

Summary Neural stimulation at high frequency induced gross changes in the ultrastructural properties and depleted the synaptic vesicles in fast axon terminals of locust extensor tibiae muscles. After a 1-h-rest the synaptic vesicle populations recovered and the ultrastructural properties of these recovering neuromuscular junctions closely resembled those of the controls.Acknowledgment. The authors wish to thank Mr M. J. Parker for invaluable help with the statistical analyses. R. P. Botham gratefully acknowledges the SRC for financial assistance.